Skin cancer is the most common cancer in the United States, with about 5 million cases every year. Melanoma is less common than other types of skin cancer, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), but it causes most of the death of skin cancer. The risk of melanoma is related to environmental factors, such as ultraviolet radiation (UVR) and genetic background.
It is noteworthy that the melanocortin-1 receptor (MC1R) is the central regulator of pigmentation and is related to the occurrence of melanoma. MC1R is a G-protein-coupled receptor, which plays a key role in regulating hair and skin pigmentation. UV can stimulate α- Melanocyte stimulating hormone（ α- MSH), while the binding of mc1R and α- MSH activates the cAMP signal, and promotes melanin synthesis, and DNA repair.
Recently, researchers from the Lerner Institute of the United States published an article entitled “AMPK photosynthetes ZDHHC13 to increase MC1R activity and suppress melanogenesis” in Cancer Res magazine. The research findings show that activating AMPK is a promising strategy to reduce the risk of melanoma, especially for redheads.
The genetic variation (RHC variant) of the melanocortin-1 receptor (MC1R) that causes human red hair color is associated with impaired DNA damage repair and increased risk of melanoma. MC1R signal transduction depends on palmitoylation and is mainly mediated by protein acyltransferase ZDHHC13. A better understanding of how ZDHHC13 is activated physiologically may help to determine the methods to prevent the occurrence of red hair melanoma.
In this study, researchers reported that AMPK phosphorylated ZDHHC13 at S208 to strengthen the interaction between ZDHHC13 and MC1R-RHC, resulting in increased palmitoylation of MC1R in red hair. Therefore, the phosphorylation of ZDHHC13 by AMPK increases the downstream signal transduction of MC1R-RHC.
AMPK activation and MC1R palmitoylation inhibited the UVB-induced transformation of human melanocytes in vitro and the formation of melanoma in C57BL/6J-MC1R-RHC mice in vivo. The importance of AMPK in MC1R signal transduction has been verified in human melanoma. The up-regulation of AMPK is related to the expression of downstream factors of MC1R signal transduction and the prolongation of patient survival.
To sum up, this study revealed the important role of AMPK-induced phosphorylation of ZDHHC13S208 in the development of melanoma. The researchers found that the activation of AMPK saved the defect of the MC1R signal caused by the MC1R RHC variant in vitro and in vivo. This study promotes our current understanding of how ZDHHC13 and MC1R signals are maintained, and provides a potential strategy to prevent the occurrence of melanoma in patients with red hair.
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Reference
Yu Sun et al. AMPK phosphorylates ZDHHC13 to increase MC1R activity and suppress melanomagenesis. Cancer Res. 2023 Jan 26;CAN-22-2595. doi: 10.1158/0008-5472.CAN-22-2595.